Wednesday, September 21, 2016

Superbugs Meet OMEGA

There is a lot of attention being paid to the emerging global health crisis of antibiotic resistant infections these days.  Today was the special session of the United Nations General Assembly that patched together a relatively bland (draft) statement looking forward to more studies to report back in two years. As my brother-in-law always says – keep your expectations low. But on the positive side, the international attention to this looming crisis can only be good. We can only hope that Europe, especially the UK, keeps moving forward with concrete plans backed up with real resources (read money) to address this problem today rather than tomorrow. What we need are the kinds of pull incentives that DRIVE AB has been discussing and that are being considered most seriously in Europe.  Of course, BARDA has not stopped in its tracks either in terms of providing push incentives as was evidenced by today’s announcement of a portfolio grant of up to $132 million the Medicines Company.

One of the problems that remains unresolved and is not addressed well anywhere is the lack of new antibiotics in the pipeline.  What I mean is that we have a science deficit that will not be overcome anytime soon given the paltry number of researchers now working in the area. The reasons behind this are multiple (read my book or follow my blog).  But a recent report from the Pew Charitable Trust outlines the problem very well and focuses on the key scientific problem facing us. Specifically, we are talking about the problem of Gram-negative superbugs with their double membrane and their extensive system of efflux pumps that either prevent antibiotics from getting into the bacteria altogether or pump the antibiotics  back out before they can kill the bacterial cells.

This brings me to the OMEGA project (Outer Membrane Efflux Gram-negative Assault).  The origin of this was a phone call I received last year from Jonathan Thomas, the chairman of the board of the California Institute for Regenerative Medicine (CIRM). CIRM is a research funding agency of the State of California focused on stem cell research.  It has a very large budget (~$3 billion).  So JT (as he is known) is familiar with research around new therapies. He is passionate about doing something concrete about the antibiotic resistance problem before it kills us all. I put him in touch with Kim Lewis and the OMEGA project was born.

The OMEGA project has as its major goal the discovery of new antibiotic candidates that can be placed into clinical development.  After our first meeting with a small group of highly skilled experts, we have developed a two-pronged approach.  The first is to develop a much better understanding of the permeation of antibiotics into Gram-negative pathogens. Others have tried this, but not with the focus we plan to apply here. We believe that small molecules (antibiotics) will fall into a few well defined categories depending on how they penetrate the bacterial cell.  Each category (or bin) will have a different set of chemical rules that must be followed to allow the compound to penetrate the bacteria more efficiently (See Lynn Silver's paper).  We believe that the tools to decipher the complex process of permeation are now available. The rules that we discover will serve to help the chemists optimize compounds to make better antibiotics. Our job is to understand these rules insofar as possible.

The second prong of our approach is to undertake the discovery of novel, natural product antibiotics using several, modern, and only recently validated methods. The two prongs come together when we have to optimize any natural product antibiotics that we discover using these methods.

So far, the OMEGA project remains a twinkle in the eyes of its originators – JT, Kim Lewis and myself.  To make the project a reality will take funding.  Raising these funds is our next step. But I am confident, based on our first meeting with true experts in these areas, that the OMEGA project will succeed where others have failed.

If we don’t provide new lead compounds, we will never have a robust pipeline of new antibiotics for the future.  And that is what OMEGA is all about.

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